Breast cancer (BCa) ranks second only to lung cancer as the leading cause of US cancer deaths in women. A common mechanism for the sustenance of breast carcinoma is the malfunction of endocrine proteins such as estrogen receptor (ER). Therapeutic interventions that capitalize on such protein malfunction have enjoyed measured success in breast cancer therapy and/or chemo-prevention. For example, selective estrogen-receptor modulators (SERMs) such as tamoxifen are the first-line therapy for treatment of hormone dependent breast cancer. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these drugs. The exact mechanisms of the acquired resistance are not completely understood. It is clear however that resistant tumors still maintain ER expression, either in the form of ER (in more than 70% of the case) or up regulation of the expression of ER, a closely related isoform ER. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat the resistant stage BCa and early stage as well. The specific focus of the studies proposed in this application is to explore the tumor ER expression state to effect a selective delivery of an independent anti-tumor chemotype, in this case histone deacetylase inhibitor (HDACi). Our choice of HDAC as a therapeutic target is informed by the fact that HDAC inhibition is a clinically validated anti-cancr strategy that is selectively cytotoxic to transformed cells. HDACi continue to stimulate immense excitement in oncology, with close to 500 clinical trials initiated to date, thus far resulting in wo clinically approved drugs, SAHA (Zolinza) and FK228 (Istodax), for the treatment of cutaneous T-cell lymphoma (CTCL). However, current HDACi have serious limitations resulting from poor biodistribution, including ineffectively low concentrations in solid tumors and off-target toxicity which is hampering clinical progress. The proposed research solves the problems of two mainstream cancer therapy agents - resistance development to estrogen-receptor modulators and lack of tumor accumulation of HDACi - to furnish a novel class targeted anti-BCa agents. If successful, the proposed research will lead to breakthroughs in BCa therapy and positively impact patients' treatment outcome.